Recent studies in the field of erection physiology have acknowledged that long-standing defective constitutive nitric oxide (NO) signaling in the penis may contribute significantly toward the pathophysiology of diverse erectile disorders including recurrent ischemic priapism, vasculogenic erectile dysfunction (ED), and penile fibrosis. The gaseous chemical NO is not just a physiologic mediator of penile erection, but it is also a homeostatic regulator involved in the steady state vascular biology of the penis. Accordingly, new directions in this research field involve investigating further this particular role of the chemical in the pathophysiology of erectile disorders. The primary hypothesis of this proposal is that "NO imbalance" occurs in the penile vasculature in association with various erectile disorders providing a molecular basis for their development. We have focused our investigation on the pathophysiology of recurrent priapism, an erectile disorder of repetitively occurring non-willful, excessive, and painful penile erection, which frequently results in permanent erectile tissue damage, erectile dysfunction, and psychological distress. We submit that specific molecular abnormalities are associated with this disorder, including 1) defective endothelial NO production sources;2) altered circulating (hemoglobin and plasma) NO delivery;and 3) increased oxidative stress leading to NO degradation. Specific aims for the proposal are: 1) to determine whether NO signaling of vascular homeostasis is defective in the penis in association with recurrent priapism;2) to investigate molecular mechanisms which contribute toward NO imbalance in the penis in association with recurrent priapism;and 3) to evaluate the effects of restoring NO bioactivity to the penis under conditions of recurrent priapism. Our proposed research work plan includes the use of experimental mouse animal models in combination with molecular and physiologic studies relevant to the NO-based signal transduction pathway in the penis and oxidative/nitrosative stress mechanisms. It is anticipated that findings produced by this study will provide a clearer understanding of the cellular and molecular mechanisms underlying recurrent ischemic priapism and provide a rational basis for its treatment. Recent studies in the field of erection physiology have acknowledged that long-standing defective constitutive nitric oxide (NO) signaling in the penis may contribute significantly toward the pathophysiology of diverse erectile disorders including recurrent ischemic priapism, vasculogenic erectile dysfunction (ED), and penile fibrosis. The primary hypothesis of this proposal is that "NO imbalance" occurs in the penile vasculature in association with various erectile disorders providing a molecular basis for their development. We submit that specific molecular abnormalities are associated with recurrent priapism including 1) defective endothelial NO production sources;2) altered circulating (hemoglobin and plasma) NO delivery;and 3) increased oxidative stress leading to NO degradation. It is anticipated that findings produced by this study will provide a clearer understanding of the cellular and molecular mechanisms underlying this disorder and provide a rational basis for its treatment.